1. Field of the Invention
This invention relates to the use of D-tagatose as a prebiotic component. It can be used as a prebiotic food, food additive or food supplement.
Tests have surprisingly shown that oral intake of the unabsorbable carbohydrate, D-tagatose, induces production of butyrate in colon. From the literature it is known that butyrate possibly has a colon cancer protective effect. Further, tests have shown that oral intake of D-tagatose stimulates the growth of beneficial lactobacilli and lactic acid bacteria in the human colon. Therefore, D-tagatose is useful as a prebiotic food to stimulate the growth of beneficial bacteria and to induce the production of butyrate. Such prebiotic food is thus presumably useful for normalizing the bacterial flora in the colon and for preventing the risk of colon cancer in human beings.
D-tagatose is a well-known keto-hexose which is useful as a reduced-calorie food sweetening and bulking agent, and as an additive in detergent, cosmetic and pharmaceutical formulations. U.S. Pat. Nos. 5,002,612 and 5,078,796 to Beeadle et al. teach processes of making D-tagatose by isomerizing a mixture containing D-galactose with a metal hydroxide in the presence of a catalyst at a relatively low temperature to form an intermediate complex, followed by neutralization with acid to yield D-tagatose.
D-tagatose is known as an anti-hyperglycaemic agent that can be used to inhibit formation of advanced glycosylation in products in mammals, as described in U.S. Pat. Nos. 5,356,879 and 5,447,917 to Zehner et al. D-tagatose also is known as a low-calorie carbohydrate sweetener and bulking agent that can be used in the preparation of sweetened edible formulations in stead of sucrose, as taught in U.S. Pat. No. 4,786,722 to Zehner.
2. Description of the Related Art
The mucosal surfaces of the intestinal tract are amongst the main sites of cell replication in the human body. In the colon the epithelial cells are exposed not only to the circulation and to the endogenous secretions of other mucosal cells, but also to the contents of the colonic lumen which is rich in food residues and the metabolic products of the micro flora. (I. T. Johnson “Butyrate and markers of neoplastic change in the colon”, European Journal of Cancer Prevention, Vol. 4, 1995) Epidemiological and animal studies suggest that dietary fat and protein may promote carcinogenesis in the colon, whereas increases in fibre and complex carbohydrates in the diet may protect against colon cancer. Colonic luminal butyrate concentrations are postulated to be the key protective component of high-fibre diets against colon cancer (O. C. Velázquez, H. W. Lederer and J. L. Rombeau 1996. “Butyrate and the Colonocyte: Implications for Neoplasia”, Digestive Diseases and Science Vol. 41, No. 4: 727–739).
Butyrate is one of the short-chain fatty acids (SCFA), i.e. the C2–5 organic acids. These compounds are formed in the gastrointestinal tract of mammals as a result of anaerobic bacterial fermentation of undigested dietary components, and are readily absorbed by the colonic epithelium. Dietary fibre is the principal substrate for the fermentation of SCFA in humans, however, intake of fibres is often low in a typical western diet. Other undigested components, like starch, proteins, contribute to the production of SCFA, but also low-molecular weight oligosaccharides, sugars, and polyols, which escape digestion and absorption in the small intestine, contribute to the production of SCFA. In the mammalian hind gut, acetate, propionate, and butyrate account for at least 83% of SCFA and are present in a nearly constant molar ratio 60:25:15 (Velazquez et al., supra).
In vitro studies on fibre and other indigestible carbohydrates in human faecal incubations indicate 3–22% butyrate, only various forms of starches and resistant starches had a butyrate proportion of 22–29% (F. Bornet, C. Alamowitch and G. Slama 1994. “Acides Gras Volatils: Des actions sur le metabolisme glucidique”, Rev Prat 44(8):1051–1055). Similarly, ileal effluents from pigs eating beet fibre and barley bran incubated in human faecal slurry in vitro incubation did not increase the proportion of butyrate beyond the 18% observed with ileal effluents from a fibre free pig diet (A. Fardet, F. Guillon, C. Hoebler and J-L. Barry 1997. “In vitro fermentation of beet fibre and barley bran, of their insoluble residues after digestion and ileal effluents”, J. Sci Food Agric 75: 315–325). In a pig study ingesting either raw potato starch, hylon starch or retrograded hylon starch, the molar proportion of butyrate was not higher than 14% at the highest level, which was in the proximal colon, and similarly the in vitro incubation showed only between 14 and 25% butyrate (mol %) (L. J. M. Martin, H. J. W. Dumon and M. M. J. Champ 1998. “Production of short-chain fatty acids from resistant starch in a pig model”, J. Sci. Food Agric. 77:71–80.
A study of fermentation of mono- and disaccharide in a human faecal in vitro system, indicated a high proportion of butyrate on fermentation of sorbitol, galacturonic acid and glucoronic acid (P. B. Mortensen, K. Holtug and H. S. Rasmussen 1988, “Short-chain fatty acid production from mono- and disaccharides in a faecal incubation system: Implications for colonic fermentation of dietary fiber in humans”, J. Nutr. 118:321–325). The findings of high butyrate with sorbitol are not confirmed on incubation with maltitol, which consists of 50% glucose and 50% sorbitol, as in vitro incubation of maltitol only indicated 10% butyrate (A. Rapaille and F. Bornet, “Maltitol, recent findings on colonic health”, FIE London 1997).
The colonic epithelium is a dynamic tissue in a state of continual renewal. Cells proliferate in the lower two-thirds of the normal colonic crypt, and cease dividing as they migrate further up the crypt. The continuous movement of cells up the colonic crypt is tightly linked to differentiation (A. Hague, A. J. Butt and C. Paraskeva 1996 “The role of butyrate in human colonic epithelial cells: An energy source or inducer of differentiation and apoptosis”, Proceedings of the Nutrition Society 55:937–943).
Butyrate appears to be of central importance to the colonic epithelium because it is the major and preferred fuel (W. E. W. Roediger 1980, “Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man”, Gut 21:793–798) and plays a role in the control of proliferation and differentiation of colonic epithelial cells. Many studies have demonstrated that butyrate is trophic to the colonic mucosa at physiological concentrations, and this is due to an acceleration of crypt cell proliferation (Johnson, supra).
In many tissues undergoing rapid turnover of cells, apoptosis is involved in the maintenance of tissue homeostasis. In the gut, where the epithelial cells are exposed to dietary carcinogens, cells undergo apoptosis as a means of eliminating damaged cells and, thus, protecting the tissue against neoplastic changes. Several in vitro studies have indicated that butyrate causes apoptosis at physiological concentrations (2–4 mM) (A. Hague and C. Paraskeva “The short-chain fatty acid butyrate induces apoptosis in colorectal tumor cell lines”, European Journal of Cancer Prevention, Vol. 4, 1995).
In contrast to the above mentioned trophic effect of butyrate on normal mucosa, the growth of neoplastic colonocytes is arrested by butyrate, which also inhibits the preneoplastic hyper proliferation induced by tumor promotor in vitro. The uncontrolled growth of cancer cell lines is stopped, and differentiation is induced by butyrate (Velazquez et al., supra).
The lactobacilli are important inhabitants of the intestinal tract of man and animals. Lactobacillus species, notably Lactobacillus acidophilus, are most often implicated in assisting the establishment of a ‘normal micro flora’, especially following antibiotic therapy. In addition, probiotic lactobacilli have been implicated in a variety of beneficial roles, including (T. R. Klaenhammer 1998, “Functional activities of lactobacillus probiotics: Genetic mandate”, Int. Dairy Journal 8:497–505): Maintenance of the normal micro flora, pathogen interference, exclusion and antagonism, immunostimulation and immunomodulation, anticarcinogenic and antimutagenic activities, deconjugation of bile acids, lactase presentation in vivo.
Another effect mentioned of lactobacillus is reduction in blood cholesterol (C. Daly, G. F. Fitzgerald, L. O'Conner and R. Davis 1998, “Technological and health benefits of dairy starter cultures”, Int. Dairy Journal 8:195–205)
A lot of studies on probiotic bacteria have shown that it is very difficult for these bacteria to colonize the human colon, that is after having stopped supply of probiotic bacteria in the diet, they disappear from faeces. This makes it more obvious to isolate possible probiotic bacteria from the human intestine (U.S. Pat. No. 5,709,857). It is even more obvious to selectively feed the lactobacillus already present in the colon (prebiotic concept).
The literature on beneficial effects and mechanism on both butyrate and lactobacillus is very abundant, so only recent review type articles are referred to in this section.